This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The emerging pathogen and class B agent West Nile virus (WNV), against which there is no approved human vaccine, is especially deadly to the elderly population, for reasons incompletely understood at the present. This proposal will define the underlying mechanism(s) of vulnerability by employing an initially broad, but subsequently more focused, examination of the sum of age- and virus-induced changes in anti-WNV immunity in a succession of mouse, monkey and human models. It is anticipated that one or more mechanisms of age-related vulnerability to WNV and, potentially (in conjunction with our concurrent studies in antipoxvirus immunity in the elderly) to other agents of bioterrorism, will be defined and/or postulated for definitive testing and correction. Specific objectives are to: 1. Establish correlates of WNV protective immunity and define mechanisms of vulnerability to WNV in old mice;2. Based upon #1, use Rhesus macaque (RM) WNV infection to study vulnerability and resistance to WNV in old non-human primates;3. Using data from 1&2 and direct tests, define the "immunological age" in elderly humans, evaluate the predictive value of this phenotype for WNV susceptibility and validate key mechanisms of immune vulnerability to WNV in elderly humans. These objectives will be accomplished by integrated efforts of a synergistic multidisciplinary and multi-institutional team from Arizona, Oregon, Texas (two sites) Louisiana and Pennsylvania. Major advances were achieved in the past project period in describing an exquisite resistance of rhesus macaques to the WNV infection, regardless of age or the CD8+ immune status, and also with regard to correcting many, if not all, of the age-related defects in immune responsiveness. These are reported in the two manuscripts listed below, respectively.